Anti-platelet therapy has been shown to reduce clinical ischemic events and improve outcomes for acute coronary syndrome (ACS) patients. Currently, the approved anti-platelet products include aspirin and thienopyridines, such as clopidogrel and ticlopidine. One of the most widely prescribed thienopyridines is clopidogrel, which is also known as Plavix®.
Physicians often prescribe a dual anti-platelet therapy, which include aspirin and a thienopyridine, such as clopidogrel, for patients who have been diagnosed with acute coronary syndromes (ACS) or for patients who are showing symptoms associated with ACS as a first line treatment. Pending further examinations, these patients may continue with this treatment or receive other treatments such as coronary artery bypass grafting (CABG) and PCI. Consistent with this practice, current ACC/AHA guidelines recommend immediate initiation of dual anti-platelet therapy of clopidogrel and aspirin after a patient is diagnosed with ACS. Similarly, patients that have received a bare metal stent or drug-eluting stent are also put on aspirin and Plavix® for an extended period of time to prevent an ischemic event.
For many patients, this dual anti-platelet therapy provides tremendous clinical benefits, and minimizes the risks of ischemic events, such as heart attack and stroke. However, for certain patients, this therapy does have problems. Side effects from the use of thienopyridines include severe neutropenia, thrombotic thrombocytopenic purpura and increased incidence of hemorrhage, including gastrointestinal hemorrhage and cerebral hemorrhage. Furthermore, it has been observed that patients receiving the dual anti-platelet therapy experience an increased need for blood transfusions and incidence of bleeding complications while undergoing surgery and other invasive procedures. This is particularly true for ACS patients who often receive surgery, such as CABG and PCI, and other invasive procedures, such as implantation of a bare metal stent (BMS) or drug-eluting stent (DES).
Due to these concerns, for many patients who undergo surgery or other invasive procedures as subsequent treatments, continuation of the dual anti-platelet therapy of aspirin and clopidogrel is not desirable. Current ACC/AHA and STS guidelines recommend cessation of clopidogrel and aspirin before any non-emergent cardiac surgical procedures in order to minimize risk of bleeding during surgery.
Further complicating the matter, aspirin and thienopyridines are both irreversible, long-acting platelet antagonists. Reversal of the inhibition of platelet function occurs only as new platelets are generated and therefore even after discontinuation of aspirin and thienopyridines, their effect lasts several days before being completely eliminated. Consequently, a patient is often required to stop the dual anti-platelet therapy and wait for five to seven days before any surgical or invasive procedure can be performed.
As a result, physicians often face the difficult choice of discontinuing clopidogrel and aspirin prior to surgery and risking a potential ischemic event in the unprotected perioperative period or delaying surgery until after the time at which clopidogrel is no longer required.
Therefore, a need exists for additional anti-platelet therapies where conventional treatments, such as thienopyridine treatment (including clopidogrel or Plavix®) cannot be used, for example, where the effectiveness of the treatment has decreased over time, where the treatment is contraindicated, or where the treatment cannot be administered to the subject (such as an orally administered therapy). Further, in view of the long-lasting and irreversible side effects of thienopyridine, a new therapy for patients who are undergoing surgery or other invasive procedures, and who have discontinued prior treatment of aspirin and thienopyridines, is needed. Such therapies would allow suppression of platelet activities prior to, during, and/or after an invasive procedure without an increased risk of excessive or irreversible bleeding. This new therapy would also maintain platelet inhibition at acceptable levels and allow for rapid restoration of platelet function after discontinuation so that patients may undergo invasive procedures without increasing the risk of bleeding complications.